Susceptibilidad a la afección neumocócica en niños y en adultos: de los efectos mendelianos de la inmunidad a los estudios genéticos poblacionales

treptococcus pneumoniae, Gram positive encapsulated bacteria, is a common colonizer of the human nasopharynx. Although frequently asymptomatic, it can migrate to sterile tissues and organs and cause non‐invasive or invasive pneumococcal disease (IPD). S. pneumoniae has evolved numerous mechanisms to evade the immune response, such as the antigenic differences of capsular polysaccharides. Currently there are evidences that suggests a high hereditary component of the host in the susceptibility to infections and in the severity with which the infection occurs. There are different types of inheritance involved in the predisposition to infection that can be classified as monogenic (a single gene involved), or polygenic (several genes involved). Primary immunodeficiencies (IDP) are a clear example of genetic predisposition to diseases with a monogenic inheritance pattern. In recent years, the incidence of PIDs has been shown to be significantly higher than previously suspected, and it has been found that some PIDs can especially predispose to pneumococcus. Demonstrating that a disease is associated with a polygenic predisposition is difficult, since, on the one hand, association studies (case‐control) with large sample sizes are required, and on the other hand, the low penetrance of each gene and their additive effects can mask the results. Studies carried out to investigate possible polygenic predispositions to diseases have been carried out by analyzing single nucleotide variations (SNV). The complement system is an important mechanism against microorganisms in human immunity. However, over or under activation can be detrimental to the host, causing autoimmune or chronic inflammatory diseases or increasing the risk for infection. Several SNVs in the complement system have been associated with chronic inflammatory diseases. However, only a few variants, other than those classified as IDP, have been associated with bacterial infections. There is currently controversy over the role of the lectin pathway (MASP‐2, MBL) in the predisposition to infection and autoimmunity. The first objective in this Doctoral Thesis has been to carry out a genetic association study to investigate the role of genetic variants of the complement system in the susceptibility to community‐acquired pneumonia (CAP), specifically to pneumococcal CAP in adults. The second objective in the present work has been the collection of clinical and epidemiological data, as well as the performance of immunological studies, in pediatric patients with severe IPD, even with only one episode, in order to analyze the incidence of classical risk factors and IDP in this population. In order to elucidate the clinical consequences of MASP‐2 deficiency, the third objective has been to analyze the presence of the p.D120G mutation in different groups of adult and pediatric patients, as well as in healthy individuals, and to analyze the causal effect of IDP produced by MASP‐2 deficiency. IX. Anexos. Summary 184 This Doctoral Thesis confirms…